tbuckley/cabot-search huggingface dataset:
HGG-38. Gliomatosis cerebri/Glioblastoma with discordant histological and molecular profiles - treatment and outcome of a pediatric patient
Authors: Virginia Harrod, Jason Morris, Winson Ho
Journal: Neuro-Oncology (2022)

Abstract Gliomatosis cerebri is no longer recognized as a distinctive pathological diagnosis, but a manifestation of diffuse glioma involving at least three cerebral lobes. Lack of understanding in this manifestation of CNS neoplasms limits treatment for this aggressive disease. Here we present a case of stabilization of disease in a pediatric patient with unusual molecular profiles normally associated with aggressive tumor behavior. A nine-year-old male presented with acute onset of right-sided vision changes, headache and numbness of the left arm and leg for one day. He also had a three-month history of an asymptomatic bump on the right temporal skull bone. MRI of the brain was significant for diffuse thickening of the cortex of the entire right hemisphere (temporal&amp;gt;frontal&amp;gt;parietal lobes). No specific enhancing lesion or restricted diffusion was noted. Histologically, the tissue had findings of diffuse low-grade astrocytoma. Molecular genetic testing was notable for TERT and EGFR mutations which are more consistent with adult type high-grade astrocytic tumors. MGMT promoter methylation array was negative. Final diagnosis was glioblastoma, IDH and H3 wildtype. All the molecular features of this tumor were high-grade with an average progression free survival of less than 12 months. Despite the lack of methylation, we opted to include alkylating agents in a maintenance chemotherapy treatment plan following radiation therapy with concurrent temozolomide. Despite poor prognostic factors, the patient is alive without signs of progression 2.5 years post-diagnosis. Targeted agents were not used in upfront treatment for this patient. This is a rare case of stabilization of disease with conventional treatment in a very aggressive tumor. This case is a rare constellation of an ‘adult-type’ molecular profile in a pediatric patient with a low grade, less aggressive behavior profile, and highlights the need to better understand this rare subtype of tumors in children.
Impact of PSMA-targeted PET/CT in the clinical management of men with advanced prostate cancer.
Authors: Matthew D Tucker, Yu-Wei Chen, Hesham Abdallah Yasin, Kristin Kathleen Ancell, Daniel Ari Barocas, Katy Beckermann, Sam S. Chang, Nancy B. Davis, Aaron Jessop, Elizabeth Kaiser, Austin Noah Kirschner, Christien Alexandre Kluwe, Amy Luckenbaugh, Kelvin A. Moses, David F. Penson, Philip Sherer, Woodson Smelser, Deborah Wallace, Kerry Schaffer, Brian I. Rini
Journal: Journal of Clinical Oncology (2022)

e17053 Background: 18 F-DCFPyL (piflufolastat F 18) is a PSMA-targeted agent FDA-approved for PET imaging in men with prostate cancer. Given the recent availability for clinical use, we sought to evaluate the impact and potential changes in management after the incorporation of 18 F-DCFPyL (PyL) PET/CT at an academic medical center. Methods: We reviewed the first 100 PyL PET/CT scans performed at the Vanderbilt-Ingram Cancer Center for men with prostate adenocarcinoma. Patient demographics, treatment history, and prior imaging results were recorded, along with PyL PET results, most recent PSA, and clinical management plans. Management changes were designated as change in systemic therapy, radiation, or surgery and were determined by two independent reviewers with a third reviewer for any discordant cases. Results: There were 100 men included with PyL PET scans dating from 9/1/21 to 12/31/21. The median age was 69 years, 76% of patients were white and 13% were black. The median Gleason sum at diagnosis was 7 (4+3), 55% of men had prior prostatectomy, and 38% had prior radiation to the prostate/pelvis. The median PSA prior to PyL PET scan was 1.86 (IQR 0.53-9.95 ng/mL), 32% of men had previous ADT exposure, and 15% were on ADT at the time of PyL PET scan. The clinical setting prior to PyL PET scan was initial staging 22%, biochemical recurrence 59%, m1HSPC 14%, m0CRPC 2%, and m1CRPC 3%. There were 16 patients who had a prior 18 F-fluciclovine within six months of PyL PET; of these 69% (11/16) had additional disease on PyL PET not previously identified. Activity in lymph nodes was observed in 48%, bone 37%, visceral sites 3%, prostate/prostate bed 46%, and 15% had no PSMA-avid disease. Clinical staging was altered after the PyL PET scan in 55% of patients, with the most common change being from BCR to m1HSPC (40/55). Clinical management was altered in 59% of cases: systemic therapy 38%, radiation planning 46%, and surgical planning 6% (Table). Conclusions: Clinical management was affected in 59% of cases after implementation of PyL PET in this retrospective, single center review. Given the rapid adoption of PSMA-targeted PET imaging agents, further studies are needed to evaluate the clinical impact of subsequent changes to management planning, as well as to develop multidisciplinary consensus statements and protocols to guide management.[Table: see text]
Disparities in palliative care utilization in cholangiocarcinoma patients: A National Cancer Database (NCDB) study.
Authors: Bennet Chun, Chang Lee, Vincent Eaton, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2022)

e24077 Background: Cholangiocarcinoma is an adenocarcinoma of the intra- and extrahepatic bile duct epithelial cells. Although cases of cholangiocarcinoma in the US are rare, there is a low 5-year survival rate for these patients. The preferred treatment option for all subtypes is surgical resection. Alternative options include palliative care (PC) treatments such as chemotherapy, radiotherapy and locoregional treatments. There are many obstacles in accurately diagnosing cholangiocarcinoma, including obtaining adequate tumor samples for histology and determining what is malignant vs. benign in patients with primary sclerosing cholangitis (an important risk factor of cholangiocarcinoma). Such delays in diagnosis can lead to delays in treatment, which in turn results in a poor prognosis and worse outcome for patients. To the authors’ knowledge, there is no current study assessing PC disparities in patients with cholangiocarcinoma. Methods: A total of 46,751 patients who had a diagnosis with cholangiocarcinoma were identified utilizing the National Cancer Database (NCDB) ICD-O-3 histology code 8160. The 5-year survival of PC use was analyzed via a Kaplan-Meier curve. Demographic factors (race, biological sex, income, facility type, insurance, geographic location, and Charlson-Deyo co-morbidity score) were studied in relation to the receipt of PC. Results: Approximately 15.16% of our cohort received PC (7,089/46,751). There was a statistically significant difference in the staging of those patients that received palliative care, with 52% of our cohort being stage IV (p &lt; 0.001). The sex of patients who received PC was equally distributed between men and women (51.0% to 49.0%). The majority of PC recipients were white (83.6%) individuals making under $63,000 (69.6%) with a reported Charlson-Deyo score of 0 (64.9%). Many patients who received PC had Medicare (57.6%) and were treated at either an academic/research program (45.4%) or at a comprehensive community cancer program (33.6%). Facility locations were predominantly located in the Mid-South Atlantic and East North Central regions, compared to the Pacific regions (56.3% vs 8.4%), and patients who received PC lived mainly in urban areas (98.2%). The median survival for PC patients was shorter compared to patients that did not receive PC (5.32 months vs 9.23 months). Conclusions: This is one of the most comprehensive studies that identifies the demographic disparities of patients who received PC for cholangiocarcinoma. The typical PC patient is a white individual with Medicare, living in an urban area in the Mid-South Atlantic and East North Central region making under $63,000. By highlighting the disparities that exist, our study can aid clinicians in addressing PC under-utilization in specific demographics to help provide more comprehensive care.
Creating diversity, equity, inclusion, and access in cancer clinical research: Drive rank and Drive score.
Authors: Maya Nicole Birhiray, Ruemu Ejedafeta Birhiray
Journal: Journal of Clinical Oncology (2022)

e13636 Background: The inequalities in improving cancer mortality rates in the United States can be ascribed to treatment disparities that are largely due to unequal access to clinical trials in cancer care, resulting in adverse clinical and economic effects. D.R.I.V.E is a five-step strategy for promoting and improving DEIA in clinical trials for minority patients based on the following steps. Methods: Appointing a clinical trial Diversity Officer, creating a RANK SCORE based on minority enrollment, Individual diversity plan, Verification of study diversity, and Elevate and Enhanced training of minority investigators and research team members. Results: Global Performance Indicators (GPIs), which rate and rank states relative to one another, shape decisions. Rankings should be reported by authors and required for publication in peer-reviewed journals and should be included in journal impact factor assessment. Conclusions: DRIVE aims to use these strategies to correct inequalities and promote the overall health of mankind, using proven principles and techniques to create meaningful improvements in cancer care and outcomes. DRIVE RANK), based on the achievement of minority participant representation relative to the epidemiology of disease, is an informational tool to evaluate DEIA efforts and provide a readily accessible measurement of the applicability of clinical data to all patient subgroups with the potential to force positive changes to promote DEIA and the health of mankind. We propose a ranking of 0-5 for diversity (Table). Establish a corporate ranking system (DRIVE SCORE) based on the diversity of clinical data from the totality of studies of the company to inform the choice of ethical investors. Studies will be ranked at the next lower rank if all criteria for next higher rank are not reached.[Table: see text]
County-Level Variation in Changes in Firearm Mortality Rates Across the US, 1989 to 1993 vs 2015 to 2019
Authors: Michelle Degli Esposti, Jason Gravel, Elinore J. Kaufman, M. Kit Delgado, Therese S. Richmond, Douglas J. Wiebe
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Firearm violence remains a critical public health challenge, disproportionately impacting some US regions. County-level variation may hold key insights into how firearm mortality rates vary across the US. <h3>Objective</h3> To model county-level changes in firearm mortality rates (total, homicide, and suicide) from 1989 to 1993 vs 2015 to 2019 and identify and characterize hot spots showing unexpected changes over time. <h3>Design, Setting, and Participants</h3> This is a cross-sectional study with 2 time points using a novel small area estimation method to analyze restricted access mortality microdata by cause of death and US county. The analysis included 3111 US counties from 49 states and the District of Columbia from January 1, 1989, to December 31, 2019. Bayesian spatial models were fitted to map geographical variation in changes in age-standardized firearm mortality rates (per 100 000 person-years) from 1989 to 1993 vs 2015 to 2019. County outliers (or hot spots) were defined as having observed rates that fell outside the 95% credible intervals of their expected posterior predictive distribution. These counties were characterized using visualization and descriptive statistics of their characteristics. Data were analyzed from June to December 2021. <h3>Exposures</h3> County of residence. <h3>Main Outcomes and Measures</h3> Five-year age-standardized mortality rates by US county, age, and cause of death for 1989 to 1993 and 2015 to 2019. <h3>Results</h3> Between 1989 and 2019, 1 036 518 firearm deaths were recorded in counties across the US. Suicide was the most common cause of firearm mortality (589 285 deaths) followed by homicide (412 231 deaths). Age-standardized rates (deaths per 100 000 individuals) for firearm deaths and suicides increased from 1989 to 1993 vs 2015 to 2019 (mean [SD] change, 0.16 [8.78] for firearm deaths and 1.21 [6.91] for suicides), while firearm homicides decreased (mean [SD] change, −0.39 [3.96]). However, these national trends were not homogeneous across counties and often varied by geographical region. The West and Midwest showed the most pronounced increases in firearm suicide rates, whereas the Southeast showed localized increases in firearm homicide rates, despite the national decreasing trend. Critical hot spots were identified in urban counties of Alabama, and firearm homicide rates (per 100 000) in Baltimore City, Maryland, almost doubled from 29.71 to 47.43, and by 2015 to 2019 it accounted for 66.7% of all firearm homicide in Maryland. By contrast, District of Columbia showed promising improvements over time, decreasing from 56.5 firearm homicides per 100 000 in 1989 to 1993 to 14.45 in 2015 to 2019. <h3>Conclusions and Relevance</h3> There was substantial variation in rates and changes in firearm deaths among US counties. Geographical hot spots may be useful to inform targeted prevention efforts and local policy responses.
Prevalence and risk factors of preoperative anemia in patients undergoing hysterectomy for gynecologic cancer.
Authors: Sagar Kamlesh Chokshi, Aliza L. Leiser, James K. Aikins, Cande Ananth
Journal: Journal of Clinical Oncology (2022)

e18800 Background: Anemia is a common preoperative finding that is associated with increased morbidity and mortality in patients with gynecologic cancers. This study identified the prevalence and risk factors associated with anemia in women undergoing hysterectomy for gynecologic cancer. Methods: The National Surgical Quality Improvement Program (NSQIP) database was queried from 2014 to 2020 for women above the age of 18 who underwent an open or minimally invasive hysterectomy and had a postoperative diagnosis of endometrial, cervical, ovarian, or fallopian tube cancer. Prevalence rates of anemia (hematocrit less than 30%) were calculated, and odds ratio (OR) with 95% confidence interval (CI) were estimated from logistic regression models adjusted for comorbidities. Results: A total of 62,708 patients were included in the analysis and 3351 (5.3%) had anemia. Mean hematocrit was 38.9 (SD 4.9). Overall, endometrial cancer was the most common diagnosis (73.1%) and mean age for all patients was 61.2 years (SD 12.1). Patients were predominantly non-Hispanic White (74.4%). Non-Hispanic Black patients were 1.98 (95% CI, 1.76 – 2.22) times at increased odds of anemia compared to non-Hispanic White patients. Similarly, Hispanic ethnicity was associated with increased odds of anemia compared to non-Hispanic White women (OR, 1.31; 95% CI, 1.14 – 1.50). Underweight patients had 1.64 (95% CI, 1.27 – 2.12) increased odds of anemia compared to normal weight patients. Compared to patients that underwent minimally invasive surgery, those that had an open abdominal hysterectomy were at over 2.7-fold increased odds (OR, 2.77; 95% CI, 2.53 – 3.04) of anemia. Those who reported greater than 10% loss of body weight in the last 6 months were 2.33 (95% CI, 5.06 – 6.81) times at increased odds of anemia. Other clinical factors associated with increased odds of anemia included metastatic cancer, American Society of Anesthesiologists (ASA) physical status classification score of 3 or more, and 2 or more comorbid conditions. Conclusions: There are multiple risk factors associated with preoperative anemia in patients undergoing hysterectomy for cancer. Identification of high-risk patients may help clinicians appropriately screen for and treat anemia prior to surgery.
EPEN-23. Interaction of epigenetic regulation and telomerase re-activation in high-risk ependymoma
Authors: Carola N Jaunecker, Dominik Kirchhofer, Sibylle Madlener, Anna Laemmerer, Lisa Gabler, Christine Pirker, Martin Piontek, Kendra Maaß, Konstanitin Okonechnikov, Bernhard Englinger, Li Jiang, Lisa Mayr, Daniel Senfter, Sabine Spiegl-Kreinecker, Natalia Stepien, Christian Dorfer, Mariella Filbin, Marcel Kool, Johannes Gojo, Walter Berger, Daniela Loetsch-Gojo
Journal: Neuro-Oncology (2022)

Abstract Ependymomas (EPN) account for 10% of pediatric CNS tumors. Among the ten subgroups characterized by DNA methylation profiling, tumors located in the supratentorial region that harbor ZFTA fusions (e.g. ZFTA-RELA), and tumors in the posterior fossa region group A (PF-A) represent the most aggressive entities. As currently therapy success relies on the extent of tumor resection and druggable targets are so far widely missing, new therapeutic approaches are urgently needed. Epigenetic dysfunction, resulting in aberrant histone modifications as well as altered DNA methylation patterns, majorly contributes to the aggressiveness of high-risk EPN. In earlier studies, we discovered that high-risk EPN is composed of a cellular hierarchy initiating from stem-cell like populations, frequently showing telomerase re-activation. Considering that epigenetic mechanisms regulate stemness maintenance and telomerase reverse transcriptase (TERT), we studied the impact of epigenetically active drugs on differentiation and telomerase re-activation in these tumors. Accordingly, we first investigated the basal expression levels of TERT and EZH2 in a panel of patient-derived high-risk EPN cell models of different subtypes (n=7). Interestingly, both, TERT and EZH2, were highly expressed predominantly in ZFTA-RELA cell models. Corroboratively, increased sensitivity of ZFTA-RELA cells towards the EZH2 inhibitor DZNep was observed in cell viability and clonogenic assays. While HDAC inhibitors were similarly active across high-risk EPN cell models, the BET inhibitor JQ1 more efficiently reduced survival of ZFTA-RELA cells. Treatment with DZNep resulted in a loss of H3K27me3 histone marks accompanied by decreased ubiquitination of H2AK119 in the investigated ZFTA-RELA cell models, and induced apoptosis indicated by PARP cleavage. Currently, impacts of direct or pharmacological EZH2 blockade on TERT promoter methylation, induction of senescence and differentiation are analyzed. Summarizing, we proof varying efficacy of epigenetically active drugs in high-risk EPN subgroups, in particular EZH2 inhibition in ZFTA-RELA cell models.
Tandem CAR-T cells targeting CLDN18.2 and NKG2DL for treatment of gastric cancer.
Authors: Hui Xu, Weiguang Li, Huixia Lv, Dongying Gu, Xiaowei Wei, Hong-jiu Dai
Journal: Journal of Clinical Oncology (2022)

4030 Background: Gastric cancer (GC) is one of most common malignant tumor which is fifth for melanoma incidence and second for mortality rates worldwide. Novel therapeutic strategies are urgently needed. Recently people are exploring the potential of chimeric antigen receptor T (CAR-T) cell therapy in GC, yet the clinical outcome is limited. Reportedly, the bispecific CAR-T cell with tandem scFvs exhibited superior response rates or synergistic response compared with CAR-T cell with single scFv. It's reported that Claudin18.2 (CLDN18.2) is the most potential target of gastric cancer. Here, we construct a novel bispecific CAR-T cells (KD-496), which simultaneously recognize NKG2D ligands and CLDN18.2, to show superior antitumor efficacy and safety in vitro and in vivo. Methods: Gastric cancer cell lines as well as GC patient tissue samples were evaluated for NKG2DL and CLDN18.2 expression. The KD-496 CAR-T cells showed antigen-specific stimulation by cytokine secretion and tumor cell cytotoxicity assay. The patient tumor tissue fragments (8 mm 3 ) were implanted subcutaneously into B-NDG mice to establish PDX models. When the tumor volume reached 50-100mm 3 , the mice received a single treatment of 5 million KD-496 CAR-T cells intravenously. The effect of KD-496 CAR-T in vivo was detected by measuring tumor volume twice a week. Results: CLDN18.2 and NKG2DL were detected on NUGC4, AGS-18.2 and MKN-28-18.2 cells and most of screened BM patient samples. The bispecific CAR-T cell KD-496 was generated with CD8 hinge region and transmembrane region, 4-1BB costimulatory region and CD3 zeta region. The KD-496 expression was &gt; 50% on the surface of T cells confirmed by flow cytometry. Co-incubation of KD-496 CAR-T cells with NUGC4 and MKN-28-18.2 cell specifically upregulates IFN-γ cytokines and strongly lysis tumor cells even at low E:T ratio (50-60% at 4:1). Strikingly, KD-496 CAR more efficiently eliminated xenograft tumors in vivo and did not exhibit significant treatment-related toxicity in the treated mice. No obvious pathological changes were found in the tested organs. Conclusions: Our work construct a tandem CAR molecule targeting two tumor-associated antigens, NKG2DL and CLDN18.2, and found that Tan-CAR-T cells（KD-496）distinctly recognize the antigens and exhibited superior antitumor effect. KD-496 CAR-T cells potently respond to GC and more efficient tumor elimination than single CAR such as KD-025 and KD-182 CAR-T cells in PDX model with no obvious safety issue. The results support future clinical trial of KD-496 CAR in patients with GC, where the need for effective treatment is great.
Convection-delivered adenoviral gene therapy reprograms the immunosuppressive glioblastoma microenvironment.
Authors: Jacob S Young, Nam Woo Cho, Ti Casey-Clyde, Raquel Santos, Kyounghee Seo, Joanna J. Phillips, Mitchel S. Berger, Tomoko Ozawa, David R. Raleigh
Journal: Journal of Clinical Oncology (2022)

2039 Background: Immune checkpoint inhibition has not improved outcomes for glioblastoma patients, and single- cell approaches reveal the glioblastoma microenvironment is largely comprised of immunosuppressive cells. We hypothesized intratumor convection enhanced delivery (CED) of adenoviral gene therapy could recruit and activate anti-tumor immune cells in the glioblastoma microenvironment. Methods: Syngeneic GL261 (3x105 cells/mouse) or SB28 glioblastoma (3 x 10 4 ) cells were implanted into the frontal lobe of immunocompetent C57BL/6J mice (18 mice/arm). Intracranial bioluminescence (BLI) and body weight (BW) measurements were used to assess glioblastoma growth and treatment toxicity, respectively. After tumor engraftment, glioblastomas were treated with conformal ionizing radiation mimicking stereotactic radiosurgery (SRS) in human patients as a positive control for tumor inhibition (18Gy/1Fx). Attenuated adeno-associated virus 9 (AAV9) vectors encoding Gfp as a negative control, or encoding experimental cytokines driving recruitment and activation of anti-tumor immune cells in other intracranial tumors ( Ccl4, Il1b, or Apoa1) were delivered using CED (2x1011 vg/mouse). Glioblastomas were collected for histologic, single-cell, and molecular analyses 5 days after treatment (6 mice/arm) and at endpoints after monitoring for survival (12 mice/arm). CED targeting was validated using AAV9-GFP and confocal microscopy. Treatment responses were assessed using H&amp;E, IHC, multiplexed cytokine assays, and single cell mass cytometry (CyTOF) to define immune cell types in the glioblastoma microenvironment. Results: Histologic analyses revealed AAV9-CCL4, AAV9-IL1B, or SRS induced glioblastoma macrophage infiltration, and AAV9-IL1B, AAV9-APOA1, or SRS induced glioblastoma T cell infiltration. AAV9-APOA1 (18.5 days versus 15 days, p &lt; 0.001) or AAV9-IL1B (16.5 days versus 15 days, p = 0.001) CED treatments prolonged median survival from SB28 allografts. Glioblastoma cytokine analysis revealed inhibition of pro-tumor cytokines (IL6, LIF) after experimental CED treatments. Systemic cytokines were minimally changed by CED treatments. CyTOF showed decreased immunosuppressive macrophage infiltration and increased CD8+ T cell or microglia infiltration of the glioblastoma microenvironment after experimental CED treatments. There was no evidence of systemic or central toxicity in any treatment condition. Conclusions: Convection-enhanced delivered of adenoviral gene therapy reprograms the glioblastoma immune microenvironment and improves survival in an immunologically “cold” syngeneic glioblastoma model.